Amino ceramide-like compounds and therapeutic methods of use

• US 20030073680A1
• Filed: 04/29/2002
• Published: 04/17/2003
• Est. Priority Date: 09/20/1995
• Status: Abandoned Application

• Current Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Shayman, James A., Radin, Norman S.
• Application Number:
  US10/134,315
• Publication Number:
  US 20030073680A1
• Time in Patent Office: Days
• US Class Current: 514/210.01
• CPC Class Codes: A61K 31/164 of a carboxylic acid with an aminoalcohol, e.g. ceramides
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: C07D 207/08 with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 295/13 to an acyclic saturated chain
• CPC Class Codes: C07D 317/54 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 319/18 Ethylenedioxybenzenes, not substituted on the hetero ring
• CPC Class Codes: C07D 321/10 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The present invention provides amino ceramide-like compounds which inhibit glucosyl ceramide (GlyCer) formation by inhibiting the enzyme GlyCer synthase, thereby lowering the level of glycosphingolipids. The compounds of the present invention have improved GlcCer synthase inhibition activity and are therefore useful in therapeutic methods for treating various conditions and diseases associated with altered glycosphingolipid levels.

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein R¹ is a phenyl group substituted with a functional group selected from the group consisting of a p-methoxy, hydroxy, methylenedioxy, ethylenedioxy, and trimethylenedioxy and cyclohexyl.

3. The compound of claim 1, wherein R² is a 5 carbon chain length alkyl residue of a fatty acid.

4. The compound of claim 1, wherein R² is a 7 carbon chain length alkyl residue of a fatty acid.

5. The compound of claim 3, wherein R² is a C₅H₁₁.

6. The compound of claim 4, wherein R² is C₇H₁₅.

7. A method for inhibiting the growth of cancer cells in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a composition comprising a compound of any of claims 1-6, wherein said cancer cells are sensitive to said compound.

8. The method of claim 7, wherein the growth of the cancer cells is inhibited by increasing the ceramide levels in the cancer cells to a toxic level.

9. A method for treating a patient having a drug resistant tumor, comprising the step of administering to the mammal a therapeutically effective amount of a composition comprising a compound of any of claims 1-6, wherein the cells of the tumor are sensitive to said compound.

10. A method for reducing tumor angiogenesis in a patient, comprising the step of administering to the mammal a therapeutically effective amount of a composition comprising a compound of any of claims 1-6, wherein said angiogenesis is sensitive to said compound.

11. A method for treating a patient having a glycosphingolipidosis disorder, comprising the step of administering to the mammal a therapeutically effective amount of a composition comprising a compound of any of claims 1-6, wherein the glycoshingolipidosis disorder is disorder associated with the presence of glucosylceramide.

12. The method of claim 11, wherein said glycosphingolipidosis disorder is selected from the group consisting of Gaucher disease, Fabry disease, Tay-Sachs, Sandhoff disease, and GM1 gangliosidosis.